CN112137985A - 壳聚糖载环丙沙星微球的制备方法 - Google Patents
壳聚糖载环丙沙星微球的制备方法 Download PDFInfo
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Abstract
本发明公开了一种壳聚糖载环丙沙星微球的制备方法。所述方法将壳聚糖和盐酸环丙沙星超声溶解于乙酸溶液中得到溶液1，司盘80超声溶解于液体石蜡中得到溶液2，按液体石蜡和乙酸溶液的体积比为3:1～4:1，司盘80和壳聚糖的质量比为25：2，混合溶液1和2，于40～60℃下搅拌乳化，缓慢滴加戊二醛溶液，搅拌交联，得到壳聚糖载环丙沙星微球。本发明制得的壳聚糖载环丙沙星微球表面较为光滑、粒径均匀分布在1～5μm之间，具有良好的抗菌性和缓释性能。
Description
技术领域
本发明属于微球载药缓释体系的制备技术领域，涉及一种壳聚糖载环丙沙星微球的制备方法。
背景技术
壳聚糖(CS)壳聚糖是一种天然多糖，可通过甲壳素脱乙酰化得到，化学名称为(1,4)-2-乙酰氨基-2-脱氧-β-D-葡聚糖，分子链上富含氨基，在医药领域应用广泛。与其它天然高分子聚合物相比，壳聚糖质子化后呈现聚阳离子性，具有优良的生物相容性，可生物降解且粘膜粘附性良好，在医药、食品、纺织、环保领域得到广泛的研究(方超.壳聚糖/蒙脱土及壳聚糖/四氧化三铁复合壳聚糖复合微球的制备及载药性能研究[D].广州：华南理工大学,2015.)。
环丙沙星具有广泛的抗菌作用，对大肠杆菌、金黄色葡萄球菌、绿脓杆菌等具有良好的抗菌效果。
乳化交联法是先将聚合物的水溶液(W)与油相(O)制备成W/O、O/W、O/W/O、W/O/W型的乳液体系后，再选择适当的途径使油水分离形成微球。根据载体材料和药物的性质、粒径要求、释放牲能和给药途径的差异，选择不同的方法制备载药微球，灵活性较强(尹中华.京尼平交联制备5-Fu-壳聚糖微球及其体外释放研究[D].南昌：南昌大学,2014.)。刘炜等用乳化交联法制备的壳聚糖载万古霉素微球对金黄色葡萄球菌的抗菌实验显示，在最初的12h，聚乳酸/壳聚糖纳米复合纤维材料能完全抑制细菌生长，但之后，细菌开始逐渐生长，最多维持20d，抑菌持久性差(刘炜等.万古霉素壳聚糖缓释微球的制备及其体外释药特性和抑菌作用研究[J].中国药房，2016,27(31):4443-4445.)。
发明内容
本发明的目的在于提供一种微球粒径均匀、缓释时间长、抗菌效果好的壳聚糖载环丙沙星微球的制备方法。
实现本发明目的的技术方案如下：
壳聚糖载环丙沙星微球的制备方法，乳化交联法制备微球，具体步骤如下：
将壳聚糖和盐酸环丙沙星超声溶解于乙酸溶液中得到溶液1，司盘80超声溶解于液体石蜡中得到溶液2，按液体石蜡和乙酸溶液的体积比为3:1～4:1，司盘80和壳聚糖的质量比为25：2，混合溶液1和2，于40～60℃下搅拌乳化，缓慢滴加戊二醛溶液，搅拌交联，离心，收集沉淀，分别用石油醚和异丙醇洗涤、离心数次，干燥，研磨，得到壳聚糖载环丙沙星微球。
优选地，所述的壳聚糖和环丙沙星的质量比为1:1～4:1。
优选地，所述的搅拌速度为500～700rmp。
优选地，所述的溶液1中，壳聚糖的浓度10mg/mL。
优选地，所述的戊二醛溶液为50％戊二醛。
优选地，所述的干燥温度为60～80℃。
优选地，所述的50％戊二醛在混合溶液中浓度为3％。
与现有的技术相比，本发明具有以下优点：
(1)本发明采用乳化交联法制备微球，成本较低，过程简单易操作，产量较高；
(2)本发明制备的微球材料粒径均匀，在1-5μm之间，药物载药率良好；
(3)本发明制备的粉末材料具有良好的抗菌性，缓释性能优异，具有持久释药性，可以用于伤口敷料，消除局部炎症反应。
附图说明
图1是壳聚糖载环丙沙星微球(壳聚糖：环丙沙星＝4：1)的扫描电子显微镜图；
图2是壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝1：1)对金黄色葡萄球菌的抗菌效果图；
图3是壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝2：1)对金黄色葡萄球菌的抗菌效果图；
图4为壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝4：1)对金黄色葡萄球菌的抗菌效果图；
图5是壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝1：1)在PBS溶液中12h，24h，72h的缓释抗菌效果图；
图6是壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝2：1)在PBS溶液中12h，24h，72h的缓释抗菌效果图；
图7是壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝4：1)在PBS溶液中12h，24h，72h的缓释抗菌效果图；
图8为壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝2：1)在PBS溶液中9d缓释后对金黄色葡萄球菌的抗菌效果图；
图9是50％戊二醛用量为2.5ml，在混合溶液中浓度为1.5％时，高速离心后得到产物图；
图10是50％戊二醛用量为7.5ml，在混合溶液中浓度为4.5％时，高速离心后得到产物图；
图11是司盘80的剂量为3ml，与壳聚糖质量比为15：2时的扫描电子显微镜图；
图12是液体石蜡和乙酸溶液的体积比为2：1时的扫描电子显微镜图；
图13是液体石蜡和乙酸溶液的体积比为4：1时的扫描电子显微镜图。
具体实施方式
下面结合实施例和附图对本发明作进一步详述。
实施例1
将0.4g 10万分子量的壳聚糖粉末溶解于40ml1％的乙酸溶液中，按壳聚糖和环丙沙星的质量比为1：1加入环丙沙星，充分溶解，再将5ml司盘80溶解于120ml液体石蜡中，分别通过超声完全溶解。混合两种溶液以搅拌速度500rmp、水浴60℃的条件下搅拌乳化30min，缓慢滴加5ml50％戊二醛，继续以搅拌速度500rmp、水浴60℃的条件搅拌交联2h，得到的悬浮液离心，得到的沉淀分别用石油醚和异丙醇洗涤、离心数次，产物置于80℃的烘箱中烘干，再使用研钵研磨得到最终产物壳聚糖载环丙沙星微球。
图2是壳聚糖载环丙沙星微球0.01g(壳聚糖：环丙沙星＝1：1)对金黄色葡萄球菌的抗菌效果图。从图中可以看出，培养24h后，抑菌圈D＝67*40mm，可知，壳聚糖载环丙沙星微球对金黄色葡萄球菌有良好的抗菌效果。
实施例2
将实施例1中的壳聚糖/环丙沙星的质量比分别改为2：1、4：1，其他步骤与实施例1相同。图1为壳聚糖载环丙沙星微球(壳聚糖：环丙沙星＝4：1)的扫描电子显微镜图，其中a图放大倍数7000，b图放大倍数为15000。从图中可以看出，微球粒径基本分布在1-5μm之间，较为均匀。不同载药比例的壳聚糖环丙沙星微球粉末对金黄色葡萄球菌的抗菌效果图，图3为壳聚糖：环丙沙星＝2：1，抑菌圈D＝40mm，图4为壳聚糖：环丙沙星＝4：1，抑菌圈D＝36mm，可见随着环丙沙星投药量的减少，抗菌效果也逐渐减弱。
实施例3
本实施例与实施例1基本相同，唯一不同的是液体石蜡和乙酸溶液的体积比为4：1。制得的壳聚糖载环丙沙星微球的SEM图如图13所示，球形良好，表面比较光滑，粘结少，与实施例1中的3：1相比无明显区别。
实施例4
取三片粘有0.01g不同载药量的壳聚糖环丙沙星微球粉末分别浸泡在PBS缓冲溶液中12h，24h，72h后取出，再做抗菌实验，观察微球粉末的缓释效果，由图5、图6、图7可知，浸泡12h，24h，72h后不同投药量粉末样品的抑菌圈直径分别为33mm、30mm、28mm(图5，1：1)，35mm、31mm、27mm(图6，2：1)，33mm、30mm、28mm(图7，4：1)。随着浸泡时间的延长，样品的抗菌效果变差，抑菌圈变小，但是仍保持抑菌效果，说明材料中的抗生素一直在释放，9d(图8，D＝25mm)后仍有释放，所以该材料已足以满足药物缓释的需要。
对比例1
本对比例与实施例1基本相同，唯一不同的是壳聚糖在乙酸溶液中浓度为5mg/mL和20mg/ml。当浓度为5mg/mL时，壳聚糖溶液浓度过低，壳聚糖粒径较小难以形成较大的、可以良好包覆环丙沙星药物的微球。当浓度为20mg/mL时，壳聚糖溶液浓度过高，壳聚糖粒径过大，小微球合在一起形成大微球，作为药物而言，在体内分散性较差。
对比例2
本对比例与实施例1基本相同，唯一不同的是50％戊二醛用量为2.5ml和7.5ml，在混合溶液中浓度分别为1.5％和4.5％，离心后得到产物量为图9和图10所示，随着戊二醛用量增加得到产物量增加，且颜色也从淡黄色加深为浅棕色。造成这种现象的原因是当戊二醛浓度很低时，单位体积内的有效浓度比较低，即使能够有效的进入到壳聚糖乳液之中，由于有效浓度不够，使得大部分的壳聚糖不能发生交联，继续以在机械搅拌状态下存在的乳液状态下存在。当高速离心时，由于没有交联成球密度未能增大，因此很难将其离心下来。而浓度过高时，交联剂过多，连结过于致密，微球中的药物难以释放，释药率低。
对比例3
本对比例与实施例1基本相同，唯一不同的是司盘80的剂量为3ml，与壳聚糖的质量比为15：2，SEM图可以看到微球之间彼此发生粘结的现象，如图11。这是因为随着Span 80的用量减小造成油相和水相之间的界面张力增大，使得微小液滴之间更加容易团聚。
对比例4
本对比例与实施例1基本相同，唯一不同的是液体石蜡和乙酸溶液的体积比为2：1。制得的壳聚糖载环丙沙星微球的SEM图如图12所示，当体积比为2：1时，微球粘结比较严重，形成较大微球，并且比较容易破损。
Claims (7)
1.壳聚糖载环丙沙星微球的制备方法，其特征在于，具体步骤如下：
将壳聚糖和盐酸环丙沙星超声溶解于乙酸溶液中得到溶液1，司盘80超声溶解于液体石蜡中得到溶液2，按液体石蜡和乙酸溶液的体积比为3:1～4:1，司盘80和壳聚糖的质量比为25：2，混合溶液1和2，于40～60℃下搅拌乳化，缓慢滴加戊二醛溶液，搅拌交联，离心，收集沉淀，分别用石油醚和异丙醇洗涤、离心数次，干燥，研磨，得到壳聚糖载环丙沙星微球。
2.根据权利要求1所述的制备方法，其特征在于，所述的壳聚糖和环丙沙星的质量比为1:1～4:1。
3.根据权利要求1所述的制备方法，其特征在于，所述的搅拌速度为500～700rmp。
4.根据权利要求1所述的制备方法，其特征在于，所述的溶液1中，壳聚糖的浓度10mg/mL。
5.根据权利要求1所述的制备方法，其特征在于，所述的戊二醛溶液为50％戊二醛。
6.根据权利要求1所述的制备方法，其特征在于，所述的干燥温度为60～80℃。
7.根据权利要求1所述的制备方法，其特征在于，所述的50％戊二醛在混合溶液中浓度为3％。
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| CN115487339A (zh) * | 2022-10-21 | 2022-12-20 | 南京晓庄学院 | 一种微交联海绵状伤口敷料及其制备方法 |
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